tbuckley/cabot-search huggingface dataset:
Using real-world evidence (RWE) in regulatory decision making: A study of 6 oncology approvals with RWE included in the product label.
Authors: Jihong Zong, Xiaolong Jiao, Lucy Pan, Sarah Castelo, Chelsey Campbell, Barb Lennert, Amanda Bruno
Journal: Journal of Clinical Oncology (2023)

6611 Background: The 21 st Century Cures Act in 2016 enhanced the FDA’s ability to include the use of real-world data (RWD) and consideration of RWE in the development and approval of new medical products. Currently, limited assessments of the use of RWE in FDA approved oncology product reviews exist in the literature. This study was conducted to determine how RWE was used in FDA decisions for oncology drug approvals between 2015 and 2022. Methods: A systematic review of FDA submission documents and product labels available on the FDA website from 2020 to 2022, in addition to an exhaustive manual search of grey literature and the results of a targeted literature search from 2015 to 2019 were used to identify RWE that were included in FDA submission documents and in approved product labels. Results: In total, 124 oncology product evaluations were reviewed in the 2020 to 2022 literature search. Twenty-nine oncology product NDAs and BLAs included RWE to support efficacy, safety, or indication, of which the majority (n=26) ultimately had RWE accepted as evidence by the FDA for the submission. In these cases, RWE was used to add context (n=16), to support the indication or safety (n=7), to provide substantial basis for indication or safety (n=2), as a statistical comparison (n=2), or for informational purposes only (n=1). Feedback from the FDA reviewers for reasons RWE studies were not considered during product approval reviews included methodology issues, sample size concerns, and omission of patient level data. Ultimately, across the 2015 to 2019 targeted literature review and the 2020 to 2022 FDA submission document review, 6 oncology product labels incorporated RWE: palbociclib, uridine triacetate, lutetium Lu 177 DOTATATE, bevacizumab-adcd, naxitamab-gqgk, and decitabine/cedazuridine. RWE was used to support the initial indication for the majority of products (n=5) and also supported label expansion (n=1). RWE was incorporated in the product label postmarketing experience section (n=3), the clinical studies section (n=2), and the warnings/precautions section (n=1). Conclusions: These results suggest that RWE has become an important part of regulatory decision-making for oncology drug approval. Twenty-six of 29 RWE studies were accepted as evidence for the submission. For the 6 oncology products that include RWE in the product label, RWE was most frequently used to support the initial indication and was included in the postmarketing experience section. These examples show consistent use of RWE since the approval of the 21st Century Cares Act and provide evidence of a promising new direction with the creation of the FDA guideline/program for RWE.
First trial of chemotherapy de-escalation in ovarian cancer (OC): A phase III randomized, open label study of niraparib maintenance after carboplatin and paclitaxel in patients with optimally debulked advanced (homologous recombination deficient) HRD high-grade ovarian cancer in first line therapy (N-PLUS/NOGGO-ov53/ENGOT-ov62).
Authors: Elena Ioana Braicu, Klaus Pietzner, Dario Zocholl, Purificación Estévez-García, Dionyssios Katsaros, Toon Van Gorp, Regina Berger, Maren Keller, Jalid Sehouli
Journal: Journal of Clinical Oncology (2023)

TPS5620 Background: OC is the fifth most common cause of death from cancer in women. More than 70% of the patients are diagnosed with advanced disease and less than 40% of women with OC are cured. Currently, the standard therapy in HRD OC is surgical debulking followed by 6 cycles of chemotherapy with subsequent maintenance treatment with poly ADP ribose polymerase (PARP) inhibitors. Within the last decades, no focus was set on the benefits of fewer cycles of chemotherapy, even though there is evidence for comparable efficacy and less toxicity in comparison to more cycles. Chemotherapies are usually associated with side effects, which can be severe and even lead to therapy discontinuation. The data available about the needed number of chemotherapy cycles is weak, especially in the context of PARP inhibition. Furthermore, patients with stage III/IV with optimal cytoreduction are underrepresented in previous studies. In the N-PLUS trial, we hypothesize that recurrence-free survival (RFS) in patients receiving 3 cycles of chemotherapy followed by maintenance with niraparib is not inferior to 6 cycles of chemotherapy followed by niraparib in advanced HRD high-grade OC patients with no visible disease following primary tumor debulking. Methods: In this multicenter, randomized, open-label study 650 patients with advanced HRD high-grade OC with no residual tumor mass following primary tumor debulking will be enrolled. Patients will be randomized 1:1 to receive either 3 cycles carboplatin + paclitaxel and maintenance therapy with niraparib (Arm A) or 6 cycles carboplatin + paclitaxel and maintenance therapy with niraparib (Arm B) for a maximum of 36 months. Randomization will be performed according to the results of the NGS analysis and stratified either to BRCAm/LOH-independent or BRCAwt/LOHhigh, FIGO stage III vs. IV, and participating countries. The primary endpoint will be RFS, secondary endpoints will be OS, TFST, TWIST, PFS2, Quality of Life and safety assessments. Clinical trial information: NCT05460000 .
10-year real-world data on acute myeloid leukemia: The paradigm of a public health center in Brazil.
Authors: Camilla Correia de A P Campos, Lais Teixeira, Marco Aurelio Salvino
Journal: Journal of Clinical Oncology (2023)

e19022 Background: Acute myeloid leukemia (AML) is a heterogeneous disease with different predominant molecular pathways. The last few years have witnessed great advances in targeted therapy. There are several trials in developed countries evaluating clinical outcomes. Nevertheless, data from low and middle-income (LMIC) countries frequently describe inferior results. Methods: This was a retrospective single-center cohort conducted in a university hospital in Northeast Brazil. We have analyzed the outcomes of all 62 patients diagnosed with AML between 2007 and 2017. Patients were classified using the European LeukemiaNet 2017 model into favorable (n=8), intermediate (n=18), and adverse risk (n= 7). 29 were not otherwise classified because of the absence of cytogenetic and/or molecular tests. We used logistic regression for data analysis assessing death as the outcome. Survival measures were estimated using the Kaplan-Meier method. The impact of bone marrow transplant (BMT) on patients eligible for intensive treatment on overall survival (OS) was assessed using a Cox proportional hazards model. Results: The median OS (mOS) of the entire cohort was 7 months (CI: 3.14-10.85). Stratifying by the risk, the mOS was shorter in patients with unknown and adverse risk (3 and 5 months, respectively) than in favorable and intermediate risk (22 and 11 months, respectively, P = 0.05). 16 (38%) patients were submitted to allogeneic BMT. We found a survival advantage (hazard ratio, HR: 0.32, 95% CI: 0.15-0.71) – p=0.005) in transplant patients, with superior median overall survival (mOS) (49 months) when compared with the chemotherapy group (6 months) ( P = 0.003). A total of 48 (77%) patients died during the follow-up and most deaths (n=39, 81%) occurred during the first year of diagnosis. Univariate analysis of clinical and laboratory characteristics found no association with death. A multivariate model including AML origin, risk stratification, and alloBMT as predictor variables demonstrated the protective power of alloBMT (table). Conclusions: Inferior outcomes found in LMIC are the result of a multifactorial scenario that reflects the absence of proper diagnostic tools, hospital infrastructure, and the lack of more effective and less toxic therapies. We suggest that patients with inadequate risk assessment should undergo consolidation with alloBMT as this remains the primary curative intervention in the real-world setting of LMIC. [Table: see text]
Effect of operative time and blood lost on overall survival after pancreaticoduodenectomy.
Authors: Hyunjee V. Kwak, Amber Chang, Peter D Peng, George Kazantsev, Austin L Spitzer, CK Chang
Journal: Journal of Clinical Oncology (2023)

e16270 Background: Blood transfusion is associated with a negative impact on cancer survival. This study aims to evaluate intra-operative time (OR time) and estimated blood loss (EBL) and their impact on survival. Methods: A retrospective review was undertaken to identify patients who had pancreaticoduodenectomy, treated at one of our 4 HPB centers of excellence for Northern California Kaiser Permanente members. All patients received their treatments between January 2015 and July 2022. The two parameters of OR time and EBL were assigned into a 2x2 grid with the creation of four separate groups. The 4 combination groups identified patients with an OR time of more than 400 minutes as time being compared and EBL of more than 600 ml as the absolute volume compared. Results: We identified 999 patients who underwent a pancreaticoduodenectomy. The mean OR time was 377 minutes, and the mean EBL was 349 ml. Portal vein resection was performed on 10.8% of patients. Neoadjuvant chemotherapy (NAT) was used in 27.8% of patients and associated with longer OR time, EBL, and portal vein resection (p&lt;.001). Patients with OR time &gt;400 minutes and EBL &gt;600 ml was associated with male, higher percentage of pancreatic/bile duct cancer, portal vein resection, a longer length of stay, re-admission at 7- and 30-days post-op, neoadjuvant chemotherapy, and adjuvant chemotherapy (Table 1). Mean overall survival for the patients with an OR time &gt;400 minutes and EBL &gt;600 ml was 37 months, while for those with an OR time &lt;400 minutes and EBL &lt;600 ml was 59 months (p&lt;.001). Conclusions: The combination of prolonged intra-operative time and blood loss is associated with decreased overall survival. The two parameters of EBL and OR time are a proxy for advanced tumors and vascular involvement gave the need for portal vein resection and higher utilization of adjuvant and neoadjuvant chemotherapy.
Racial and ethnic disparities in risk of second primary malignancies among diffuse large B-cell lymphoma survivors.
Authors: Pragati Gole Advani, Kristopher Attwood, Megan Herr, Sheeba Habeeb Ba Aqeel, Pallawi Torka
Journal: Journal of Clinical Oncology (2023)

7567 Background: Previous studies have shown an increased risk of second primary malignancies (SPMs) among diffuse large B-cell lymphoma (DLBCL) survivors; however, this has not been comprehensively examined by race/ethnicity. We utilized a large population-based database to examine disparities in SPM risk by race/ethnicity. Methods: From 17 United States population-based Surveillance, Epidemiology and End Results (SEER) program cancer registry areas, we identified 57,262 ≥12-month first-primary DLBCL survivors diagnosed between 2000-2019. Standardized incidence ratios (SIRs) and accompanying 95% confidence intervals (CIs) quantified SPM risk by race/ethnicity (non-Hispanic White, Black, Asian/Pacific Islander [API] and Hispanic), compared with the general population. Results: Overall, we observed 4,719 SPMs after DLBCL representing a 1.2-fold significantly increased risk (95% Confidence Interval [CI] = 1.16-1.23) compared to the general population and an excess of 23 cases per 10,000 person-years. SIRs for all second cancers combined varied significantly by race/ethnicity with APIs and Hispanics presenting higher overall SPM risk [SIR API : 1.42 (CI = 1.27-1.59), and SIR Hispanic : 1.31 (CI = 1.19-1.43)] compared to the White or Black patients [SIR white : 1.17 (CI = 1.13-1.21), SIR Black : 1.16 (CI = 1.03-1.30)] (p-heterogeneity &lt; 0.001). Heterogeneity by race/ethnicity in SIRs was even more pronounced in DLBCL survivors diagnosed at a younger age, those who were ≥5 years into their survivorship, those who had received chemotherapy, or those who had received no radiation as their initial treatment. Although SIRs for SPM was significantly higher for advanced stage DLBCL survivors (compared to those with a localized/regional disease), heterogeneity by race/ethnicity in SPM risk was significant regardless of the stage. Results from site specific analyses reported significantly higher overall SIRs for second hematological malignancies compared to solid cancers [SIR hemat : 3.52 (CI = 3.22-3.85), and SIR solid : 1.08 (CI = 1.04-1.11)]. Patterns by race/ethnicity also varied significantly by second cancer type, particularly for second primary anal cancer, Hodgkin’s lymphoma (HL), and Acute Non-Lymphocytic Leukemia (ANLL) (p &lt; 0.001 for each). Strikingly elevated SPM risks (SIRs &gt; 10) were observed for second primary anal cancer, HL and ANLL among the Black patients, and HL among the APIs and Hispanic DLBCL survivors, compared to the white patients. Conclusions: Using a large-scale population-based data, we observed substantial disparities in SPM risk by race/ethnicity, with patients belonging to minority groups experiencing higher risks. SPMs have emerged as an important challenge for DLBCL survivors, therefore, further research to understand drivers of the observed race/ethnicity heterogeneity is warranted.
Posterior reversible encephalopathy syndrome in malignancy: Hypercalcemic storm?
Authors: Mehndi Dandwani, Suma Sri Chennapragada, Shivani Sharma, Kamleshun Ramphul, Petras Lohana
Journal: Journal of Clinical Oncology (2023)

e17559 Background: Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiological entity characterized by seizures, headaches, altered mental status and visual anomalies associated with vasogenic edema affecting the parietal-occipital lobes on brain magnetic resonance imaging. PRES is rarely described in hypercalcemia of malignancy although multiple mechanisms have been postulated in various case reports. Hence, we conducted this study to evaluate whether there is an increased risk of PRES with hypercalcemia of malignancy. Methods: We analyzed the 2016-2020 National Inpatient Sample (NIS) and extracted patient data with a diagnosis of ovarian cancer, lung cancer, multiple myeloma (MM), breast cancer, diffuse large B-cell lymphoma (DLBCL), and secondary bone cancer. Cases with a history of primary hyperparathyroidism, vitamin D intoxication and familial hypocalciuric hypercalcemia were excluded. The presence of hypercalcemia and PRES were estimated (per 10,000 cases), and their respective adjusted odds ratios (aOR) were calculated via multivariate regression analysis. Results: We identified 1,775 PRES cases in 3,781,899 cancer patients studied. Patients with breast cancers (26 per 10,000 hypercalcemia cases vs. 4 per 10,000 cases with no hypercalcemia, aOR 4.523, 95% CI 3.418-5.984, p &lt; 0.01), ovarian cancers (41 per 10,000 hypercalcemia cases vs. 8 per 10,000 cases with no hypercalcemia, aOR 5.224, 95% CI 3.075-8.875, p &lt; 0.010), and secondary bone neoplasms (14 per 10,000 hypercalcemia cases vs. 5 per 10,000 cases with no hypercalcemia, aOR 2.160, 95% CI 1.671-2.793, p &lt; 0.01) exhibited a statistically significant increased outcome of PRES in association with hypercalcemia. The presence of hypercalcemia among lung cancer patients (aOR 0.755, 95% CI 0.451-1.263, p = 0.284), MM (aOR 1.005, 95% CI 0.751-1.346, p = 0.973), and DLBCL (aOR 1.393, 95% CI 0.806-2.408, p = 0.236) did not show a valid odds ratio for PRES. Conclusions: Our study found a higher association of PRES among hypercalcemia patients with ovarian cancer, breast cancer and secondary bone neoplasms. Prompt recognition of PRES and hypercalcemia-directed treatment can allay the morbidity related to PRES. While our study was limited in quantifying the cut-off values of hypercalcemia causing PRES, designated protocols entitled solely to determining serum calcium thresholds in these cancers warranting rigorous treatments are needed. PRES’s association with hypercalcemia in female-dominant cancers also paves way for further studies looking into the influences of sex hormones and hormonal therapies on the development of PRES with hypercalcemia.
Chemotherapy induced peripheral neuropathy (CIPN) and biomarkers of gut microbial translocation in long-term survivors of testicular germ cell tumors.
Authors: Michal Chovanec, Katarina Kalavska, Jana Obertova, Patrik Palacka, Katarina Rejlekova, Zuzana Sycova-Mila, Valentina De Angelis, Zuzana Orszaghova, Peter Lesko, Daniela Svetlovska, Beata Mladosievicova, Jozef Mardiak, Barbora Vlkova, Michal Pastorek, Peter Celec, Michal Mego
Journal: Journal of Clinical Oncology (2023)

e17032 Background: Survivors of testicular germ cell tumors (GCT) may suffer from long-term treatment induced peripheral neuropathy. We hypothesized markers of gut microbial translocation after chemotherapy and/or radiotherapy may be contributing factors of peripheral neuropathy. Methods: GCT survivors (N = 194) from National Cancer Institute of Slovakia completed the EORTC QLQ Chemotherapy-Induced Peripheral Neuropathy (CIPN20) questionnaires during their annual follow-up visit at 10-year median (range 2-25). Biomarkers of gut microbial translocaion and dysbiosis (GMT) lipopolysaccharide (LPS), high mobility group box-1 (HMGB-1), d-lactate and sCD14 were measured from peripheral blood obtained during the same visit. Upon obtaining the scores from questionnaires per recommended guidelines, each score was correlated with biomarkers of GMT scored as as high or low (above and below median). Survivors were treated with orchiectomy only (N = 30), cisplatin-based chemotherapy (N = 135), radiotherapy to the retroperitoneum (N = 14) or both chemotherapy and radiotherapy (N = 10). Results: GCT survivors with higher vs lower plasma levels of HMGB-1 had worse overall CIPN20 score (median ± SD = 18 229.0 ± 13 644.2 vs 17 387.0 ± 5106.6 p = 0.048). Patients with higher vs lower plasma HMGB-1 also had worse motor function (9.0 ± 1.8 vs 8.0 ± 2.3, p = 0.036). Sensory and autonomy subscales of CIPN20 qestionaire did not show significant association with HMGB-1 (both P &gt; 0.05). There was no significant difference in CIPN20 symptom burden associated with LPS, d-lactate and sCD14 (all P &gt; 0.05). Conclusions: HMGB-1 may serve as a promising biomarker of CIPN20 in long-term cancer survivors. Proinflammatory pathways are suggested as underlying mechanism of CIPN. Furhter research and larger patient cohorts are needed to explore the pathogenesis of CIPN in GCT survivors.
The Normal Risk Ovarian Screening Study (NROSS): Twenty-one year update.
Authors: Chae Young Han, Karen H. Lu, Deepak Bedi, Enrique Bedia, Therese Bartholomew Bevers, Laura L. Holman, Leroy Leeds, Cara Amanda Mathews, Georgia Anne-Lee McCann, Richard G. Moore, Matthew Schlumbrecht, Brian Slomovitz, Daniel Tobias, Marian Yvette Williams-Brown, Jinsong Liu, Beverly Carol Handy, Zhen Lu, Jacob Bedia, Steven J Skates, Robert C. Bast
Journal: Journal of Clinical Oncology (2023)

5522 Background: The Normal Risk Ovarian Screening Study (NROSS) tested a two-stage screening strategy in post-menopausal women at conventional hereditary risk where significantly rising CA125 prompted transvaginal sonography (TVS) and abnormal TVS prompted surgery to detect ovarian cancer. Methods: A total of 7,856 healthy postmenopausal women were screened annually for a total of 50,596 women-years in a single arm study ( NCT00539162 ). Serum CA125 was analyzed with the Risk of Ovarian Cancer Algorithm (ROCA) each year. If risk was normal ( &lt; 1:2000), women returned in a year. If risk was elevated ( &gt; 1:500), TVS was undertaken immediately and if risk was intermediate, CA125 was repeated in 3 months, risk recalculated, and the participant re-triaged. An average of 2% of participants were referred to TVS annually. Results: Thirty-four patients were referred for operations detecting 15 ovarian cancers and 2 borderline tumors with 12 in early stage (I-II). In addition, 7 endometrial cancers were detected with 6 in early stage. Thus, the positive predictive value (PPV) of the NROSS trial was 50% (17/34) for detecting ovarian cancer and 74% (25/34) for any cancer, far exceeding the minimum acceptable study endpoint of 10% PPV. As 4 ovarian cancers and 2 borderline tumors were diagnosed within a year of each participant’s last normal risk, the sensitivity for detecting ovarian and borderline cancer was 74% (17/23) and 70% of ROCA-detected cases (12/17) were in stage I-II. NROSS screening reduced incidence of late stage (III-IV) disease by 34% compared to the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) control arm and by 30% compared to US SEER values. Results of our NROSS trial contrast dramatically with those of the recently reported UKCTOCS that showed only a modest 14% early-stage shift, underlying a lack of reduction in mortality. Across multiple randomized trials of mammography, those trials that demonstrated at least a 20% late-stage incidence reduction had a significant mortality reduction, whereas those with less of a stage shift did not. Conclusions: An elevated ROCA, characterized by a significantly rising CA125, prompted referral of 2% of participants to TVS each year and required only 2 operations to detect each case of ovarian cancer, indicating that CA125 used in this way is adequately specific for effective screening. While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV and marked stage shift support further development of this strategy. Clinical trial information: NCT00539162 .